Human tissues secrete low molecular weight phospholipases A2 (named “secreted PLA2s” or “sPLA2s”; EC 3.1.1.4) which catalyse the hydrolysis of phospholipids at the sn-2 position to release fatty acids (such as arachidonic acid) and lysophospholipids. Lysophospholipids and fatty acids are biologically active as precursors of potent bioactive lipid mediators. Such lipid mediators are important players in inflammation, cancer and neurodegenerative diseases (Kudo and Murakami 2002; Nakanishi and Rosenberg, 2006; Sun et al., 2007). Besides the possible role of human sPLA2s in lipid mediator production, accumulated evidence indicate that these enzymes are likely to participate in innate immunity, especially in the first line of host defence against bacteria and other pathogens (Lambeau and Gelb, 2008; Nevalainen et al., 2008). Human sPLA2s share common characteristic features: numerous disulfide bonds, low molecular masses (13-18 kDa), catalytic histidinyl and aspartyl residues, and millimolar concentrations of calcium requirement for optimal catalytic activity. However, the different human sPLA2 paralogs are not closely related isoforms since the amino acid identity between any two of them is comprised between 15% to 50% Furthermore, the different paralogs have very distinct enzymatic properties (Singer et al., 2002) as well as distinct tissue distribution, regulation of expression and emerging biological functions (Murakami et al., 2010).
The family of human sPLA2s comprises so far nine catalytically active enzymes and two catalytically inactive sPLA2-like proteins (XIIB and otoconin-95). They have been classified as groups (G) IB (Seilhamer et al., 1986), IIA (Kramer et al., 1989; Seilhamer et al., 1989), IID (Ishizaki et al., 1999), IIE (Suzuki et al., 2000), IIF (Valentin, 2000b), III (Valentin, 2000a), V (Chen et al., 1994), X (Cupillard et al., 1997) and XIIA (Gelb et al; 2000), XIIB (Rouault, M., et al. 2003) and otoconin-95 (see also for reviews Schaloske and Dennis, 2006; Lambeau and Gelb, 2008 and Murakami et al., 2010). The GIB sPLA2 (pancreatic type sPLA2) and GIIA sPLA2 (inflammatory type sPLA2) were the two first human sPLA2s identified in the 80's (Verheij et al., 1981 and Kramer et al; 1989). The other members of the human sPLA2 family were cloned in the late 90's and after (see for review Valentin et al., 2000c and Murakami et al., 2010).
Different enzymatic properties and unique tissue distribution and/or cellular localizations of these sPLA2s suggest distinct physiological role(s) for each enzyme (see for reviews Lambeau and Gelb, 2008 and Murakami et al., 2010). Some appear to play a role in several inflammatory diseases, such as groups IIA and V (Gilroy et al., 2004; Triggiani et al., 2005) and some exhibit bactericidal properties against Gram-positive and/or Gram-negative bacteria, such as groups IIA, X, V, XII, IIE, IB, IIF (Koduri et al., 2002; Lambeau and Gelb, 2008).
In fact, the different human sPLA2s exert highly specialized and non redundant functions in different tissues and biological contexts (Murakami et al., 2010). Indeed:                the different sPLA2s are expressed in a limited number of tissues and cells, they can be found at different locations in a single tissue, and their expression is differentially regulated according to the disease stages (Murakami et al., 2010); e.g., detection of high levels of GIIA sPLA2 at various inflamed sites suggests its involvement in pathogenesis of the inflammatory responses; its concentration in serum and tissues correlates with disease severity in several immune-mediated inflammatory pathologies (Kudo and Murakami, 2002; Nevalainen et al., 2008; Menschikowski et al., 2006);        some sPLA2s have high and specific enzymatic activities toward certain phospholipids while other sPLA2s have very low activities towards many if not all types of phospholipids (Singer et al., 2002);        some few sPLA2s have the capacity to hydrolyze lipoproteins and produce lipid mediator release from cellular membranes (Singer et al., 2002 and Sato et al., 2008);        some sPLA2s, whatever they are highly or poorly enzymatically active, can bind to different soluble and membrane-bound proteins (Lambeau et al., 2008);        there is emerging evidence indicating that some sPLA2s exert different and even opposite roles within the same tissue in vivo; e.g., both GIIA and GV sPLA2s are proatherogenic (Bostrom et al., 2007; Webb et al., 2003; Rosengren et al., 2006 and Jonsson-Rylander et al., 2008), while GX sPLA2 appears to be anti-atherogenic (Ait-Oufella et al., 2009); in addition, GIIA sPLA2 is proinflammatory while GV is anti-inflammatory in a mouse model of rheumatoid arthritis (Boilard et al., 2010);        contrary to GIIA sPLA2, GIID sPLA2 appears to be anti-inflammatory in murine models of colitis and multiple sclerosis (von Allmen et al., 2009).        
It appears from the foregoing that human sPLA2s are currently considered as functionally distinct isoforms with different and sometime opposite biological roles.
In malaria-infected humans, abnormally elevated levels of circulating phospholipase A2 activity have been observed in severe cases (Vadas et al., 1992 and 1993). In fact, the phospholipase A2 activity observed by Vadas et al. is attributed to the human GIIA sPLA2, since the murine monoclonal antibodies 9C1 and 4A1 used by Vadas et al. (1992) are specific for the GIIA sPLA2, and the synovial type group II PLA2 detected by Vadas et al. (1993) is known as being the human GIIA sPLA2 (see Nevalainen et al., 2005). Vadas and his colleagues have also disclosed that a recombinant human PLA2 (in fact GIIA sPLA2) selectively lyses human erythrocytes parasitizited with P. falciparum and suggested that high level of endogenous circulating PLA2 (i.e., GIIA sPLA2) may contribute to hemolysis of parasitized erythrocytes in patients with malaria (Vadas et al., 1992), but they have not provided any data supporting these statements.
Five hundred million clinical cases of malaria are reported each year and mortality estimates range between 0.7 and 2.7 million. The vast majority of cases presents a non-specific febrile illness that is relatively easily terminated, but a minority of cases progresses to severe, life-threatening disease (WHO, Management of Severe Malaria, 2000. A practical handbook, 2nd ed. Geneva: World Health Organisation). It is now currently accepted that severe malaria is an extremely complex multi-process and multi-system disorder. In human, the disease is caused by protozoan parasites of the genus Plasmodium: P. falciparum, P. malariae, P. ovale and P. vivax. The life cycle of these human malaria parasites is essentially the same: first, sporozoites enter the bloodstream, and migrate to the liver. Then, they enter the liver cells (hepatocytes), where they multiply into merozoites, rupture the liver cells, and escape back into the bloodstream. Then, the merozoites enter red blood cells (erythrocytes), where they develop into ring forms, then trophozoites (a feeding form), then schizonts (a reproduction form), and then back into merozoites.
P. falciparum is the major cause of mortality, mostly through two main complications: cerebral malaria and severe anaemia. A central feature of P. falciparum infection is sequestration of mature forms (schizonts) of parasitized erythrocytes within the microvasculature of the major organs of the body, predominantly in brain, heart, lungs and small intestine. The events resulting in the development of cerebral malaria are multi-factorial, encompassing dynamic interactions between at least three processes: sequestration of parasitized erythrocytes in the brain, haemostasis and inflammation (Van der Heyde, 2006).
Diagnosis of malaria involves identification of the malaria parasite or its antigens in the blood of the patient. It can be performed by microscopy methods (e.g., by peripheral smear examination or Quantitative Buffy Coat (QBC) test), by immunoassays for malaria antigens (e.g., using rapid diagnostic tests (RDTs)) or by Polymerase Chain Reaction assays. However, the efficacy of the diagnosis depends on many factors, such as the different forms of the four Plasmodium species, the different stages of erythrocytic schizogony (asexual multiplication in the erythrocytes), the quantitative content of parasites in the blood (parasitemia), the persisting viable or non-viable parasites in the blood and the sequestration of the parasites in the tissues.
To date, there is no rapid and accurate method to assess the risk of developing severe and/or cerebral malaria due to P. falciparum. Only certain clinical symptoms such as hypoglycaemia, severe anaemia or high parasitemia, particularly when they are combined in a patient, can alert on possible complication, sometimes too late.
Many different antimalarial drugs are available to prevent and/or treat malaria, including schizonticides on erythrocytic forms of Plasmodium, such as amino-4-quinolines (e.g., chloroquine), amino-alcohols (e.g., quinine), sesquiterpens (e.g., artemisinin) and antimetabolites, schizonticides on the intra-hepatic forms of Plasmodium and gametocytocides, such as amino-8-quinolines (e.g., primaquine), endo-erythrocytic schizonticides active on endoerythrocytic trophozoites, such as quinine (which remains the standard anti-malarial drug in the management of severe forms of malaria), and combination thereof. However, parasite resistance to some antimalarial drugs is an increasingly serious problem.
Consequently, it appears from the foregoing that there is a need of developing new method of diagnosis of malaria, particularly P. falciparum malaria, and new treatments.